ABSTRACT Myeloproliferative neoplasms (MPNs) are clonal hematologic diseases characterized by the aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. More than 20,000 new patients are diagnosed in the USA each year, and in a substantial portion of these patients disease progression leads to transformation to secondary acute myeloid leukemia (sAML), a much more aggressive and therapeutically-refractive disease. Patients who develop sAML have a poor prognosis with an average survival time after transformation of less than five months. The clonal evolution of MPN to sAML is driven by acquisition of additional co-operating genetic mutations. While advances in genome sequencing technology have elucidated the genetic background of MPN, the contribution of specific genetic events to sAML transformation is not well understood and do not seem to be explained by the individual genetic alterations that characterize the disease. My laboratory has taken a particular interest in studying the mechanisms underlying post-MPN sAML transformation because the disease invariably proves fatal, and any findings that improve the diagnosis and treatment of these patients would represent a significant advance. One such event involves chromosomal deletions of the short arm of chromosome 6, which contains the JARID2 gene. We show conditional deletion of Jarid2 in mouse models accelerates development of MPN or leads to disease progression to sAML depending on the context, and genetic inhibition of JARID2 in CD34+ cells from MPN patients facilitates engraftment in immunodeficient mice and transmission of patient pathologies. Our preliminary data establish JARID2 as a bona fide hematopoietic tumor suppressor. The motivation for this proposal is to understand the mechanisms by which JARID2 exerts this function in MPN. We hypothesize that JARID2 functions as a hematopoietic tumor suppressor by restricting self-renewal in lineage-committed hematopoietic progenitor cells and restraining oncogenic JAK/STAT signaling. We will examine this through the following Specific Aims; ? Determine the mechanisms by which JARID2 represses self-renewal in progenitors. ? Define mechanisms through which JARID2 functions as a tumor suppressor. ? Examine the unique requirement for JARID2 suppression in myelofibrosis. Understanding how JARID2 functions is critical for improving the clinical outcomes of sAML patients and identifying patients at risk for transformation, while also serving as a more general paradigm for genetic progression of MPN to sAML. In this proposal, we will leverage contemporary techniques with novel mouse models to comprehensively understand the mechanisms of how JARID2 functions as a tumor suppressor, and elucidate new precision medicine strategies for MPN and sAML patients.